The Psychophysiology Of Fear And Anxiety

恐惧和焦虑的心理生理学

• 批准号: 6982715
• 负责人: Christian Grillon
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6982715
• 关键词: NMDA receptors; anxiety; anxiety disorders; association learning; behavioral /social science research tag; benzodiazepines; brain imaging /visualization /scanning; clinical research; computer simulation; conditioning; disease /disorder proneness /risk; family genetics; fear; functional magnetic resonance imaging; human subject; model design /development; personality; psychological models; psychological shock; psychopathology; psychopharmacology; psychophysiology; psychotropic drugs; startle reaction; stimulus /response

Our research program is devoted to the study of normal and abnormal emotions with a strong emphasis on fear and anxiety. This research is conducted using psychophysiological, psychopharmacological, and brain imaging techniques. The major areas of investigation include: 1) development of human models of fear and anxiety; 2) research on the relationship between associative learning and emotional reactivity to aversive stimuli; 3) studies of personality and temperamental dimensions of psychopathology; 4) investigations of the effects of psychotropic medications on fear and anxiety in healthy individuals and in clinical groups; 5) identification of the early manifestations of psychiatric illnesses using family studies. Although the experimental approach is restricted to humans, this program of research is strongly influenced by theories and methods from animal analogues of emotion, motivation, and associative learning. Thus, the research relies on efforts to translate findings from animal research into human experimentation and studies of psychopathology. This report focuses on three main areas of interest: 1. Studies of explicit cue fear and contextual fear as models for phasic fear and generalized anxiety, respectively 2. Psychopharmacologic investigations 3. Development of experimental models of human fear and anxiety states 4. High-risk studies 1. Explicit cued fear and contextual anxiety This series of projects focuses on anxiety, as opposed to fear. Fear is associated with a clearly identifiable, imminent threat, whereas anxiety is a generalized fear without object, an apprehensive anticipation of future potential threats. Our working hypothesis is that fear and anxiety can be modeled by cued fear and contextual fear, respectively. The distinction between cued fear and contextual anxiety was first made in fear conditioning studies in animals. Cued fear is elicited by an explicit stimulus (e.g., a light) that predicts a noxious stimulus (e.g., a shock). Contextual fear is caused by the experimental context (i.e., the cage, the experimental room) where an aversive experiment took place. We showed that a similar distinction could be made in human studies (Grillon & Davis, 1997). Several features make contextual fear an appealing model of anxiety (Grillon 2002, in press). Given the potential relevance of contextual fear for our understanding of anxiety disorders and the paucity of human research in this area, we are pursuing several areas of investigations focusing on contextual fear. The first one examines factors that are involved in the modulation of contextual fear. We have developed a protocol to assess the role of predictability on contextual fear using instructed fear procedures. Results showed that contextual fear is increased by unpredictability as long as the aversive event is sufficiently unpleasant. We are currently following-up on these findings in three areas. One investigates brain mechanisms mediating cued fear to signaled shocks and contextual anxiety to unpredictable shock in an fMRI study. Preliminary findings indicate reduced activation in medial prefrontal structures during unpredictable shocks. A second investigation assesses the effects of psychopharmacological agents. A third area explores the relevance of these findings to psychopathology by investigating contextual fear in individuals diagnosed with an anxiety disorder or selected for low or high trait anxiety. Prliminary evidence shows that high trait anxious subjects and patients with anxiety disorders show increased contextual fear. Another factor that affects contextual fear is fear conditioning. Fear conditioning is adaptive because it makes aversive events predictable. We recently reported that cued fear learning deficits were associated with increased contextual fear (Grillon, 2002), suggesting that symptoms of generalized anxiety may be secondary to basic associative learning impairments. Two ffeatures emerged in subjects showing poor cued fear conditioning: 1) high trait anxiety and 2) elevated physiological arousal at the time of testing. These results emphasize the role of attentional factors in the formation of conditioned responses, the subsequent learning of emotional responses, and the development of anxiety. 2. Psychopharmacologic investigations Our study relies on the startle reflex to measure fear and anxiety. Startle is potentiated by fear in both humans and animals. In rodents, this so-called 'fear-potentiated startle reflex' effect is reduced by drugs that reduce human anxiety such as the benzodiazepines. However, human studies with benzodiazepines have been contradictory. While two studies reported that benzodiazepines reduced fear-potentiated startle, we have been unable to confirm this effect in a study that included four experiments (Baas et al. 2002). We recently pointed out issues in psychopharmacology studies with the startle reflex (Grillon and Baas, 2002). One issue is the difficulty in separating the anxiolytic from the sedative effects of benzodiazepines. Another issue is that benzodiazepines have been tested on cued fear models, while contextual fear models may be more relevant (Grillon, 2002). We are currently testing the effect of alprazolam on cued fear and contextual fear. Benadryl is used as a non-anxiolytic sedative control drug. Results show that the benzodiazepine alprazolam reduced contextual fear but not cued fear. The inability to extinguish intense fear memories is a significant clinical problem. Finding procedures or treatments that facilitate extinction of fear memories is of paramount importance. We are currently examining whether D-cycloserine, a partial agonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor, facilitates extinction. The rationale for this study is that if NMDA receptor antagonists block the acquisition of fear conditioning and of extinction, it is possible that NMDA receptor agonists facilitate this type of learning. Facilitation of extinction would be therapeutically useful. Recently, D-cycloserine was found to produce a dose-dependent facilitation of extinction of conditioned fear in the rat, when assessed with fear-potentiated startle. Our study examines whether the clinically important process of extinction can also be enhanced by D-cycloserine in humans. 3. Development of experimental models of human fear and anxiety states One important aspect of our program of research is to develop procedures to study fear and anxiety in humans. Despite important recent progress, we have become increasingly dissatisfied with traditional fear conditioning protocols. There are two main issues. Conditioned responses are weak (i.e., they extinguished rapidly) and they are not well retained over time. In addition, the stimuli used in these studies are somewhat unsophisticated (e.g., geometric shapes presented on a monitor). These problems limit the development of meaningful fear conditioning procedures, more particularly for psychopharmacology and contextual fear studies. We have embarked on a project that uses computer-generated virtual reality to investigate fear conditioning and have recently documented for the first time context conditioning in virtual environment (Baas et al 2004).4. High-risk studies We are involved in two studies examining risk factors for psychiatric disorders. One study is the continuation of a NIDA grant that was given to the present PI when he was at Yale University. The investigation looks at two different familial pathways to drug addiction, antisocial personality and anxiety. The second project is a collaborative study with Dr. Myrna Weissman (Columbia University) examining psychophysiological risk-factors for depression in children and grand-children of individuals with major depression.

我们的研究项目致力于正常和异常情绪的研究，重点是恐惧和焦虑。本研究采用心理生理学、心理药理学和脑成像技术进行。主要研究领域包括：1)人类恐惧和焦虑模型的发展；2)联想学习与厌恶刺激情绪反应的关系研究；3)精神病理学人格与气质维度的研究；4)调查精神药物对健康个体和临床群体的恐惧和焦虑的影响；5)利用家庭研究识别精神疾病的早期表现。虽然实验方法仅限于人类，但这一研究项目受到动物情感、动机和联想学习类似物的理论和方法的强烈影响。因此，这项研究依赖于将动物研究结果转化为人类实验和精神病理学研究的努力。本报告主要关注三个主要领域：1。显性线索恐惧和情境恐惧分别作为阶段恐惧和广泛性焦虑模型的研究精神药理学研究人类恐惧和焦虑状态实验模型的发展高危研究这一系列项目关注的是焦虑，而不是恐惧。恐惧与明确可识别的迫在眉睫的威胁有关，而焦虑是一种没有对象的普遍恐惧，是对未来潜在威胁的忧虑预期。我们的工作假设是，恐惧和焦虑可以分别通过暗示恐惧和情境恐惧来模拟。暗示恐惧和情境焦虑的区别最初是在动物的恐惧条件反射研究中提出的。暗示性恐惧是由一个明确的刺激（如光）引发的，它预示着一个有害的刺激（如电击）。情境恐惧是由进行厌恶实验的实验环境（如笼子、实验房间）引起的。我们表明，在人类研究中也可以做出类似的区分（Grillon & Davis, 1997）。有几个特征使情境恐惧成为一种有吸引力的焦虑模型（Grillon 2002, in press）。鉴于情境恐惧与我们理解焦虑症的潜在关联，以及在这一领域人类研究的缺乏，我们正在进行几个领域的调查，重点是情境恐惧。第一项研究考察了与情境恐惧调节有关的因素。我们已经制定了一项协议来评估可预测性在情境恐惧中的作用，使用指导恐惧程序。结果表明，只要厌恶事件足够令人不快，情境恐惧就会因不可预测性而增加。我们目前正在三个领域对这些发现采取后续行动。一项研究在功能磁共振成像研究中研究了大脑机制对信号性电击的暗示恐惧和对不可预测的电击的情境性焦虑。初步研究结果表明，在不可预测的电击中，内侧前额叶结构的激活减少。第二项调查评估了精神药理学药物的作用。第三个领域通过调查被诊断为焦虑障碍或被选择为低或高特质焦虑的个体的情境恐惧，探索这些发现与精神病理学的相关性。初步证据表明，高特质焦虑受试者和焦虑障碍患者表现出增加的情境恐惧。另一个影响情境恐惧的因素是恐惧条件反射。恐惧条件反射是适应性的，因为它使厌恶事件可预测。我们最近报道暗示恐惧学习缺陷与情境恐惧增加有关（Grillon, 2002），这表明广泛性焦虑症状可能继发于基本联想学习障碍。在暗示恐惧条件反射较差的受试者中出现了两个特征：1)高特质焦虑和2)测试时生理唤醒升高。这些结果强调了注意因素在条件反应的形成、随后的情绪反应学习和焦虑发展中的作用。2. 我们的研究依靠惊吓反射来测量恐惧和焦虑。无论是人类还是动物，恐惧都会加剧惊吓。在啮齿类动物中，这种所谓的“恐惧增强惊吓反射”效应被苯二氮卓类药物等减轻人类焦虑的药物所减弱。然而，对苯二氮卓类药物的人体研究一直存在矛盾。虽然有两项研究报告说苯二氮卓类药物减少了恐惧增强的惊吓，但我们无法在一项包括四项实验的研究中证实这一效果（Baas et al. 2002）。我们最近指出了惊吓反射在精神药理学研究中的问题（Grillon和Baas， 2002）。一个问题是很难将抗焦虑药与苯二氮卓类药物的镇静作用分开。另一个问题是，苯二氮卓类药物已经在暗示恐惧模型上进行了测试，而情境恐惧模型可能更相关（Grillon, 2002）。我们目前正在测试阿普唑仑对暗示恐惧和情境恐惧的影响。苯海拉明被用作非抗焦虑镇静控制药物。结果表明，苯二氮卓类药物阿普唑仑减少了情境恐惧，但没有减少暗示恐惧。无法消除强烈的恐惧记忆是一个重要的临床问题。找到有助于消除恐惧记忆的程序或治疗方法至关重要。我们目前正在研究n -甲基- d -天冬氨酸（NMDA）受体上甘氨酸调节位点的部分激动剂d -环丝氨酸是否促进灭绝。这项研究的基本原理是，如果NMDA受体拮抗剂阻断恐惧条件反射和消退的习得，那么NMDA受体激动剂可能促进这种类型的学习。促进灭绝在治疗上是有用的。最近，d -环丝氨酸被发现对大鼠的条件性恐惧产生剂量依赖性的消退促进作用，当评估恐惧增强惊吓时。我们的研究考察了临床上重要的灭绝过程是否也可以通过d -环丝氨酸在人类中增强。3. 开发人类恐惧和焦虑状态的实验模型我们研究项目的一个重要方面是开发研究人类恐惧和焦虑的程序。尽管最近取得了重大进展，但我们对传统的恐惧调节协议越来越不满意。主要有两个问题。条件反应是很弱的（也就是说，它们很快就消失了），而且它们不会随着时间的推移而很好地保留下来。此外，这些研究中使用的刺激有些简单（例如，显示器上呈现的几何形状）。这些问题限制了有意义的恐惧调节程序的发展，尤其是精神药理学和情境恐惧研究。我们已经开始了一个项目，使用计算机生成的虚拟现实来调查恐惧条件反射，最近首次记录了虚拟环境中的情境条件反射（Baas et al 2004）。高危研究我们参与了两项检查精神疾病危险因素的研究。其中一项研究是NIDA资助的延续，该资助是现任PI在耶鲁大学时获得的。这项调查着眼于两种不同的家庭成瘾途径，反社会人格和焦虑。第二个项目是与Myrna Weissman博士（哥伦比亚大学）的合作研究，研究重度抑郁症患者的子女和孙辈患抑郁症的心理生理风险因素。